DESCRIPTION: (Adapted from the Applicant's Abstract.) The avian inner ear is a useful model for studying the growth and development of the auditory and vestibular systems. One fundamental question concerns the regulation of growth and survival of the inner ear. In sensory cells and neurons one of the mechanisms regulating growth, survival, and synapses during development is the expression of excitation. This expression can be governed by variables extrinsic to the cell (e.g., innervation and growth factors) which in turn regulate mechanisms intrinsic to the cell (e.g., DNA transcription and protein modification). In light of this the present project will begin examining: 1) how interactions between hair cells and cochleovestibular ganglion (CVG) neurons regulate the development of excitation, and 2) how the development of excitation affects the growth, the survival, and the death of these cells. The whole-cell tight-seal recording technique will be used to measure the acquisition of voltage-gated currents in hair cells and neurons exposed to various conditions in vitro. Initially, the acquisition of ionic currents will be studied in the CVG, because the developmental data are incomplete. Subsequent experiments will focus on how neurotrophins (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) affect the survival and growth of the CVG in vitro. Using these data as a basis, the acquisition of voltage-gated currents will be measured in response to neurotrophins. Studies of hair cells will consider questions dealing with the extrinsic and intrinsic regulation of excitation.Experiments will examine how afferent innervation affects the development of ionic current in vitro and how the development of ionic currents may influence synaptogenesis. Immunohistochemistry will be used to follow the development of the synaptophysin molecule in conjunction with ionic current development. Studies of intrinsic mechanisms will examine whether functional expression of voltage-gated currents results from the transcription of a new gene or the post-translational modification of protein channels. The long term objectives of this project are to understand the cellular and molecular processes that regulate excitation in developing hair cells and CVG neurons, and to understand how this excitation affects growth, survival, and synaptogenesis in these cells. The results will provide insights into: causes of sensorineural deafness, regulation of CVG neurons by growth factors, and proteins involved with synaptogenesis.